Towards Photoswitchable Foldamers for the Remote Control of Catalysis Across Membranes

Abstract

Conformational change plays an integral role in biological systems, with several classes of biomolecules using conformational change to translate local inputs into spatially remote outputs. This natural communication mechanism has inspired the development of dynamic foldamer systems. These systems respond to external stimuli to deliver remote spectroscopic or functional outputs using conformational change in the form of reorganisation of intramolecular hydrogen bonding networks. In particular, ethylene-bridged oligo(thio)urea foldamers are attractive systems because they are achiral, populate conformational space broadly, and have vast potential for functionalisation with stimuli-responsive groups and output sites. Biological membranes play an essential role in the compartmentalisation of cells and in the interaction of a cell with its environment. Owing to the complexity of biological membranes, simplified model membrane systems formed from amphiphiles have emerged as a useful platform for the study of dynamic foldamers in the membrane phase.

This PhD thesis presents work towards the development of a dynamic ethylene-bridged oligo(thio)urea foldamer system with photoswitchable hydrogen bond directionality for the remote control of catalysis across membranes. Chapter 2 explores the development of ethylene-bridged oligo(thio)urea foldamers with fluorine
conformational probes and presents studies of the conformation of these systems in solution using 19F NMR spectroscopy. Pleasingly, for many of the foldamers studied, fluorine probes at the N-terminus and C-terminus were distinguishable in the 19F NMR spectra recorded at membrane-compatible temperatures. In some systems, more complex conformational behaviour was detectable in the 19F NMR spectra, and this led to postulation of two concurrent mechanisms for global hydrogen bond directionality reversal in these foldamers. Chapter 3 explores the insertion and behaviour of these ethylene-bridged oligo(thio)urea foldamers in the membrane phase. Chapter 4 details progress towards the development of ethylene-bridged oligo(thio)urea foldamers with photoswitchable hydrogen bond directionality, where conformational change hides or reveals a remote catalytic site. A series of photoswitchable foldamers with various photoswitch functionalities, foldamer (thio)urea side-chains, and catalytic capping groups were synthesised, and VT NMR was used to gain insights into the conformation of these systems in solution. A photoswitchable foldamer for the remote control of N-Me imidazole catalysis was the most promising system, and efforts to exploit this foldamer as a photoswitchable catalytic system in solution are described. Finally, preliminary results towards the application of this foldamer for photoswitchable N-Me imidazole catalysis across a membrane are showcased.

Overall, this work provides valuable insights towards the use of photoswitchable ethylene-bridged oligo(thio)urea systems as communication devices in membranes and as controllers in remote catalysis applications.

Date of Award	17 Jun 2025
Original language	English
Awarding Institution	University of Bristol
Supervisor	Jonathan Clayden (Supervisor)